DESCRIPTION (provided by applicant: Cocaine addiction is a chronic relapsing disorder in which subjects episodically administer the drug and ultimately transition from nondependent drug use to the compulsive drug use of addiction. A progressive increase in the frequency and intensity of cocaine use, and a high propensity to relapse after abstinence are two of the major behavioral phenomenon that characterizes the development of cocaine addiction. Despite major advances in understanding the neurobiological mechanisms underlying the transition to cocaine dependence, there are no pharmacological treatments for cocaine dependence. Recently, deep brain stimulation of the subthalamic nucleus has been proposed has a surgical strategy for obsessive-compulsive disorders, but it has never been tested in preclinical models of compulsive drug taking and drug seeking. The subthalamic nucleus, a cerebral structure belonging to the basal ganglia and classically associated with motor control, is critically involved in key cognitive processes that become dysfunctional in subjects with drug addiction. The overall objective of this proposal is to use a new, potentially groundbreaking therapeutic approach for the treatment of cocaine addiction using an innovative neurosurgical approach that has shown remarkable results in other brain and mental disorders, associated with highly relevant animal models of compulsive cocaine intake and relapse to cocaine seeking. Preliminary results show that lesion of the subthalamic nucleus limits the escalation of cocaine intake in dependent rats, and that deep brain stimulation of the subthalamic nucleus decreases the motivation for cocaine in rats. Unknown is whether deep brain stimulation of the STN will reverse the escalation of cocaine intake and prevent relapse to cocaine seeking in dependent rats. The specific objectives of this proposal are to determine whether it is possible to reverse the escalation of cocaine (SpA1), and to prevent drug-, stress-, and cue-induced reinstatement to cocaine seeking (SpA2) using deep brain stimulation in the subthalamic nucleus in cocaine dependent rats. These studies will provide new findings on the role of the subthalamic nucleus in the compulsivity associated with cocaine dependence and may open new avenues for the development of innovative treatments of drug addiction in general. PUBLIC HEALTH RELEVANCE: Despite major advances in understanding the neurobiological mechanisms underlying the transition to drug addiction there are no pharmacological treatments available. The overall objective of this proposal is to use new, potentially groundbreaking therapeutic approaches for cocaine addiction using deep brain stimulation of the subthalamic nucleus, associated with highly relevant animal models of compulsive cocaine intake and relapse to cocaine seeking. These studies will provide new findings on the neurobiological substrates of compulsive cocaine taking and craving, have direct translational implications for drug abuse, and may open new avenues for the development of innovative treatments of drug addiction in general.